title: A TLR6 polymorphism is associated with increased risk of Legionnaires' disease.
abstract: Legionella pneumophila (Lp), the etiologic agent of Legionnaires' disease (LD), is an important cause of community-acquired and nosocomial pneumonia. However, the host immune and genetic determinants of human susceptibility to Lp are poorly understood. Here we show that both TLR6 and TLR1 cooperate with TLR2 to recognize Lp in transfected HEK293 cells. We also perform a human genetic association study of 14 candidate single-nucleotide polymorphisms in Toll-like receptors (TLRs) 1, 2 and 6 in 98 LD cases and 268 controls from the Netherlands. No polymorphisms in TLR1 or TLR2 were associated with LD. A TLR6 polymorphism, 359T>C (rs5743808), was associated with an elevated risk of LD in genotypic and dominant (odds ratio (OR) 5.83, P=7.9 × 10(-5)) models. The increased risk in persons with 359 TC or CC genotypes was further enhanced among smokers. In a multivariate model, 359T>C was associated with a higher risk of LD (OR 4.24, P=0.04), than any other variable, including age and smoking. Together, these data suggest that the human TLR6 variant, 359T>C, is an independent risk factor for LD.
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Misch
authors.forename: A
authors.initials: A
authors.lastname: Verbon
authors.forename: J M
authors.initials: JM
authors.lastname: Prins
authors.forename: S J
authors.initials: SJ
authors.lastname: Skerrett
authors.forename: T R
authors.initials: TR
authors.lastname: Hawn
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D007877:Legionnaires' Disease / Q000453:epidemiology / Q000235:genetics*; D008875:Middle Aged; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D012907:Smoking; D051194:Toll-Like Receptor 1 / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051216:Toll-Like Receptor 6 / Q000235:genetics*
chemical_list: C495342:TLR2 protein, human; C495368:TLR6 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6